It is known to prepare N-acyl-hydroxy aromatic amines, e.g., N-acetyl-para-aminophenol (APAP), by acetylating the corresponding hydroxy aromatic amine, e.g. para-aminophenol, with an acetylating agent such as an anhydride, e.g., acetic anhydride. However, this reaction may cause problems such as the difficulty of mono-acetylating the amine group, oligomerization of the hydroxy aromatic amine, and color body formation. Nonetheless, the APAP made by this reaction is an important commodity of commerce, being one of the most widely used over-the-counter analgesics.
In U.S. Pat. No. 4,524,217 there is disclosed a novel process for the preparation of N-acyl-hydroxy aromatic amines, in general, and N-acetyl-para-aminophenol (APAP), in particular. The APAP is formed by a two-step process in which the first step involves reacting 4-hydroxyacetophenone (4-HAP) with a hydroxylamine salt in a base to obtain the ketoxime of the ketone (4-HAP oxime), and then subjecting the ketoxime to a Beckmann rearrangement in the presence of a catalyst to form APAP. Although various materials can be used as the Beckmann rearrangement catalyst, U.S. Pat. No. 4,524,217 discloses preferred use of thionyl chloride in liquid sulfur dioxide. The entire content of U.S. Pat. No. 4,524,217 is herein incorporated by reference.
Although sulfur dioxide has been found to be an excellent solvent for the Beckmann rearrangement of 4-HAP oxime to APAP or acetaminophen, there are certain characteristics of sulfur dioxide which are disadvantageous. For one, SO.sub.2 is toxic. Accordingly, extraordinary precautions must be taken to handle and contain the sulfur dioxide and such precautions obviously require specialized equipment. For example, centrifuges do not adequately contain sulfur dioxide and therefore cannot be used for separation of the crude solid APAP product from the sulfur dioxide reaction liquor. Consequently, such separation must be accomplished by filtration with equipment that is more expensive to purchase and operate than a centrifuge. Furthermore, centrifugation is inherently suited for continuous processing, whereas filtration is not. Additionally, SO.sub.2 is corrosive and requires expensive metallurgy. Use of SO.sub.2 as solvent may also lead to the formation of metallic contaminants from the processing equipment. Such contaminants may affect reaction rates and/or lead to the formation of by-products. Obviously, since APAP is an analgesic for human consumption, the product should be as pure as possible, and, thus, minute impurities from corrosion products are definitely not desirable. Removal of corrosion products from the APAP adds to the operating costs. Moreover, the SO.sub.2 must be pressurized for use in the liquid state. Added costs for pressurized equipment and operating are the result.
Another disadvantage with the prior two-step process of producing APAP from 4-HAP by first forming the 4-HAP oxime and then subjecting the oxime to Beckmann rearrangement with thionyl chloride in SO.sub.2 is that the oxime is prepared in water and must be recovered by chilling the aqueous oximation product to crystallize the oxime. The crystallized oxime must then be collected and dried prior to Beckmann rearrangement. The dried oxime is then fed to the APAP reactor via a hopper system. This arrangement requires solids crystallization, collection, drying, storage, and handling and the consequent use of additional and expensive equipment.
Accordingly, it would be advantageous to provide an alternative solvent to SO.sub.2 for use in the Beckmann rearrangement of 4-HAP oxime to APAP. Such a solvent should be less toxic, less volatile, and less corrosive than SO.sub.2. The solvent must also provide good yields of APAP and provide for the formation of a pure APAP product. It is therefore the primary objective of the present invention to provide an alternative solvent to SO.sub.2 in the above-described Beckmann rearrangement reaction, which solvent is less toxic, less volatile, and less corrosive, and which reduces capital costs and can greatly reduce the handling and operating costs of the two step process of forming APAP from 4-hydroxyacetophenone.